ABSTRACT The defining neuropathologic lesions of Alzheimer's disease (AD) are amyloid-??plaques and tau neurofibrillary tangles, both of which appear many years before the onset of symptoms of cognitive impairment. The overarching goal of this proposal is to evaluate a novel PET tracer, known as [F18] T807, that detects the tau neurofibrillary tangles. We will address three specific contexts in which tau PET could potentially provide critical information useful in clinical AD research by identifying stages of T807 retention that reflect the levels and extent of PHF tau according to the established Braak staging scheme: 1) The identification of age- associated medial temporal lobe PHF-tau that is consistent with Braak Stage I/II, the slowly accumulating form that begins in the third decade of life, but in later years may possibly correlate with more subtle cognitive capacities or have predictive value for eventual development of impairment, perhaps when combined with biomarker evidence of A??deposition; 2) The identification of a neocortical PHF-tau cut point of positivity that indicates an impaired stage of cognitive and clinical function, which when evaluated as a continuous variable is closely correlated with phenotypic features of the illness; 3) A determination of the links between deposition of tau and other biomarkers of AD, including amyloid-?, additional measures of neurodegeneration such as volumetric MRI, CSF tau, and measures of large-scale network disruption measured with fcMRI. This proposal builds on our previous work and existing multidisciplinary collaborations to develop clinically relevant, highly sensitive methods for tracking i) early tau deposition that may be linked to early impairment and ii) neocortical tau deposition that is hypothetically linked to dementia (Aim 1), to illuminate the relationship between more malignant, anatomically specific tau deposition that relates to local and generalized volume loss and network connectivity breakdown (Aim 2), and to relate directly in vivo for the first time the joint evolution of brain tau and amyloid-??deposition throughout the life span (Aim 3).